NO330338B1 - Indolylalkylamine derivatives, processes for their preparation and their use - Google Patents

Description

This invention relates to indolylalkylamine derivatives as 5-hydroxy-tryptamine-6-ligands, methods for their preparation, pharmaceutical preparations containing them and their use.

Various disorders of the central nervous system, such as anxiety, depression, motor disturbances, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin. Serotonin is located in the central and peripheral nervous system and is known to influence many types of conditions, including psychiatric disorders, motor activity, food intake behaviour, sexual activity and neuroendocrine regulation, among others. The effects of serotonin are regulated by the different 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (eg 5-HT1 A), the 5-HT2 family (eg 5-HT2A), 5-HT3-, 5-HT4-, 5-HT5-, 5 -HT6 and 5-HT7 subtypes.

The newly identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned and the extensive distribution of its mRNA has been reported. The highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 areas of the hippocampus. Lower levels of 5-HT6 receptor mRNA are seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity that several antipsychotic agents have for the 5-HT6 receptor, in addition to its mRNA localization in the striatum, olfactory tubercle and nucleus accumbens, suggests that some of the clinical effects of these compounds may be mediated via this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential benefit in the treatment of certain SNS disorders, such as anxiety, depression, epilepsy, OCD, ADD, migraine, cognitive memory enhancement (for example for the treatment of Alzheimer's disease), sleep disorders, food intake disorders (for example anorexia or bulimia), neurodegenerative disorders (for example stroke or head trauma), panic attacks, withdrawal from drug abuse (for example cocaine, ethanol, nicotine or benzodiazepines), schizophrenia, or the like, or in the treatment of certain gastrointestinal disorders, such as irritable bowel syndrome.

It is therefore an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of many different disorders of the central nervous system which are related to, or affected by, the 5-HT6 receptor.

It is another object of this invention to provide pharmaceutical preparations which are useful for the treatment of disorders in the central nervous system which are related to, or affected by, the 5-HT6 receptor.

It is a feature of this invention that the compounds provided can also be used to further study and elucidate the 5-HT6 receptor.

These and other objects and features of the invention will appear more clearly from the detailed description below.

The present invention provides an indolylalkylamine derivative of formula I

where

Q is SO2,

n is an integer of 2 or 3,

R 1 and R 2 are each, independently, H, halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy substituted with phenyl;

R 3 and R 4 are each, independently, H or C 1 -C 6 -alkyl,

R 5 and R 6 are each, independently, H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with phenyl, or R 5 and R 6 may, together with the atom to which they are attached, form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally substituted with C 1 -C 6 alkyl or COOH;

R7 is H,

Ra is an imidazo[1,2-a]pyridine, imidazo[2,1-b][1,3]thiazolyl or benzo[d]imidazo[2,1-b][1,3]thiazole ring system optionally substituted with 0-3 substituents selected from halogen and C1-C6 alkyl;

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

The present invention also provides methods for the production of the above-mentioned compounds, and preparations which are useful in the therapeutic treatment of disorders in the central nervous system which are related to, or affected by, the 5-HT6 receptor.

The invention also relates to the use of the above-mentioned compounds.

The 5-hydroxytryptamine-6-(5-HT6) receptor is one of the last receptors to be identified by molecular cloning. Its ability to bind a large number of therapeutic compounds used in psychiatry, coupled with its interesting distribution in the brain, has stimulated considerable interest in new compounds capable of interacting with, or influencing, the said receptor. Considerable efforts are being made to understand the possible role that the 5-HT6 receptor has in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. For this purpose, compounds which exhibit binding affinity to the 5-HT6 receptor are being diligently searched for, both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of disorders of the central nervous system, see e.g. C. Reavill and D.C. Rogers, Current Opinion in Investigational Drugs, 2001, 2(1 ):104-109, Pharma Press Ltd.

It has now surprisingly been found that indolylalkylamine derivatives of formula

I exhibits 5-HT6 affinity. The aforementioned amine derivatives can advantageously be used as effective therapeutic agents for the treatment of disorders in the central nervous system (CNS) which are associated with, or affected by, the 5-HT6 receptor. Accordingly, the present invention provides indolylalkylamine derivatives of formula I

where

Q is SO2,

n is an integer of 2 or 3,

R 1 and R 2 are each, independently, H, halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy substituted with phenyl;

R 3 and R 4 are each, independently, H or C 1 -C 6 alkyl,

R5 and R6 are each, independently, H, C1-C6-alkyl-, d-C6-alkyl substituted with phenyl, or R5 and R6, together with the atom to which they are attached, form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally substituted with C1-C6- alkyl or COOH;

R7er H,

R8 is an imidazo[1,2-a]pyridine, imidazo[2,1-b][1,3]thiazolyl or benzo[d]imidazo[2,1-b][1,3]thiazole ring system optionally substituted with 0 -3 substituents selected from halogen and C1-C6 alkyl;

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

As used in the specification and claims, the term halogen means Br, Cl, I or F.

When any of the foregoing substituents represent or contain an alkyl substituent group, this may be linear or branched, and may contain up to 6, more preferably up to 4, carbon atoms.

Examples of R 1 and R 2 are, independently, hydrogen, halogen (such as fluorine, chlorine, bromine), C 1 -C 6 alkyl (e.g. methyl), hydroxy and C 1 -C 6 alkoxy (e.g. methoxy), for example when the substitution is in the 5 and/or 6 and/or 7 position.

An example of n is 2.

An example of R8 is 6-chloroimidazo[2,1-b][1,3]thiazol-5-yl.

Each R 3 or R 4 present may be the same or different, for example one R 3 may be H, the other CH 3 .

Pharmaceutically acceptable salts can be any acid addition salt formed from a compound of formula I and a pharmaceutically acceptable acid, such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandel, succinic, fumaric, acetic, lactic, nitric, sulphonic, p-toluenesulphonic, methanesulphonic acid, and the like.

Compounds according to the invention can be in the form of esters, carbamates or other conventional prodrug forms, which are generally functional derivatives of the compounds according to the invention, and which can easily be converted into the active group according to the invention, in vivo. The various conditions described above can be treated with a compound of formula I, according to the invention. Metabolites of the compounds according to the present invention, defined as active types produced by introducing these compounds into a biological system, can also be mentioned.

The compounds according to the invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. A professional in the field will know that

one stereoisomer may be more active or exhibit beneficial effects when enriched relative to the other stereoisomer(s), or when separated from the other stereoisomer(s). In addition, the person skilled in the art will know how the mentioned stereoisomers are to be separated, enriched or selectively produced. Accordingly, the present invention encompasses compounds of formula I, the stereoisomers thereof, and the pharmaceutically acceptable salts thereof. The compounds according to the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.

The compounds of formula I, where n is 2 are preferred. Another group of preferred compounds of formula I are those compounds where R 8 is 6-chloro-imidazo[2,1-b][1,3]thiazol-5-yl.

More preferred compounds according to the invention are the compounds of formula I, where Q is SO2, n is 2 and R7 is H. Even more preferred compounds are those compounds of formula I where Q is SO2, n is 2, R7 is H and Ra is 6-chloroimidazo [2,1-b][1,3]thiazol-5-yl.

Among the preferred compounds according to the invention are: 2-{1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indol-3-yl}ethylamine, 2-{1-[(imidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indol-3-yl}ethylamine, {2-[1 -(6-chloroimidazo[ 2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1-(6-chloroimidazo[2,1-b][1 ,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}dimethylamine, benzyl{2-[1-(6-chloroimidazo[2,1-b][1,3]thiazol-5- sulfonyl)-1H-indol-3-yl]ethyl}amine, 1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-3-(2-pyrrolidin-1- ylethyl)-1H-indole, 1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-3-[2-(4-methylpiperazin-1-yl)ethyl]-1H -indole, 1 -(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-3-(2-piperidin-1 -ylethyl)-1H-indole, benzyl{2-[ 1 -(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1 H -indol-3-yl]ethyl}methylamine, {2-[1 -(6-chloroimidazo[2 ,1 -b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}phenethylamine, 1 -{2-[1 -(6-chloroimidazo[2,1-b][ 1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}pyrrolidine-2-carboxyl re,

2-[1-(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]-1-methylethylamine, (R)-2-[1 -(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]-1-methylethylamine, (S)- 2-[1-(6- chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]-1-methylethylamine, 2-[1-(2-chloroimidazo[2,1-a] pyridine-3-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[1-(2,6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-1H- indol-3-yl]ethylamine, 2-[1-(2-chlorobenzo[d]imidazo[2,1-b][1,3]thiazol-3-sulfonyl)-1H-indol-3-yl]ethylamine , {2-[1-(2-chloroimidazo[2,1-a]pyridin-3-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1-(2,6-dichloroimidazo[ 2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1 -(2-chlorobenzo[d]imidazo[2,1 -b ][1,3]thiazol-3-sulfonyl)-1H-indol-3-yl]ethyl}methylamine,

{2-[1-(2-chloroimidazo[2,1-a]pyridin-3-sulfonyl)-1H-indol-3-yl]ethyl}dimethylamine, {2-[1-(2,6-dichloroimidazo[ 2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}dimethylamine, {2-[1 -(2-chlorobenzo[d]imidazo[2,1 -b ][1,3]thiazol-3-sulfonyl)-1H-indol-3-yl]ethyl}dimethylamine,

2-[5-chloro-1-[6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5-chloro- 1 -(2-chloroimidazo[1,2-a]pyridin-3-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5-chloro-1-(2,6-dichloroimidazo[2,1 -b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5-chloro-1-(2-chlorobenzo[d]imidazo[2,1-b] [1,3]thiazol-3-sulfonyl)-1H-indol-3-yl]ethylamine,

2-[1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-5-methoxy-1H-indol-3-yl]ethylamine, 2-[1-(6- chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl-6-methoxy-1H-indol-3-yl]ethylamine, 2-[5-bromo-1-(6-chloroimidazo[2,1 -b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5-benzyloxy-1-(6-chloroimidazo[2,1-b][1,3] thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine,

2-[1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-5-methyl-1H-indol-3-yl]ethylamine, 2-[1-(6 -chloroimidazo[2,1 -b][1,3]thiazole-5-sulfonyl)-6-methyl-1H-indol-3-yl]ethylamine, 2- [1 -(6-chloroimidazo[2,1 - b][1,3]thiazole-5-sulfonyl)-7-methyl-1H-indol-3-yl]ethylamine, 3-(2-aminoethyl)-1-(6-chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl)1H-indol-5-ol, 2-[1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-5- fluoro-1H-indol-3-yl]ethylamine, 2-[1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-6-fluoro-1H-indole- 3-yl]ethylamine, 1-(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-3-(2-morpholin-4-ylethyl)-1H-indole,

3-{1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-fluoro-1H-indol-3-yl}propan-1-amine,

the stereoisomers thereof, or the pharmaceutically acceptable salts thereof.

This invention also provides methods for preparing compounds of formula I, the methods comprising one of the following:

a) to react a compound of formula B

where n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein, with a suitable sulfonylating agent, containing the group:

R8-Q-

where R 8 is as defined above and Q is SO 2 ; the reactants being protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups, which gives a corresponding compound of formula I; or b) removing a protecting group from a compound of formula I, wherein R5 is a protecting group, yielding a corresponding compound of formula I, wherein

NR5R6er-NHR6;

or

c) to react a compound of formula (C):

where n, R-i, R2, R3, R4, R7, Rs and Q are as defined herein and L is a leaving group, such as halogen, for example Br, with an amine of formula HNR5R6, giving a corresponding compound of formula I ;

or

d) converting a compound of formula I, which has a reactive substituent group, into another compound of formula I;

or

e) converting a basic compound of formula I into an acid addition salt, or vice versa;

or

f) isolating an isomer of a compound of formula I from a mixture of isomers;

or

g) converting an azide of formula (D)

where n, Ri, R2, R3, R4, R7, Rs and Q are as defined herein,

to a corresponding compound of formula I, where R5 and R6 are both H.

The invention also relates to a method for producing a compound of formula Id

where

n is an integer of 2 or 3,

R 1 and R 2 are each, independently, H, halogen, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 alkoxy, or C 1 -C 6 alkoxy substituted with phenyl;

R 3 and R 4 are each, independently, H or C 1 -C 6 alkyl,

R 5 and R 6 are each, independently, H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with phenyl, or R 5 and R 6 may be taken together with the atom to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally substituted with C 1 -C 6 alkyl or COOH;

R7er H,

R8 is an imidazo[1,2-a]pyridine, imidazo[2,1-b][1,3]thiazolyl or benzo[d]imidazo[2,1-b][1,3]thiazole ring system optionally substituted with 0 -3 substituents selected from halogen and C1-C6 alkyl; which comprises reacting a compound of formula XVIII

where n, R-i, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above for formula Id, with a sulfonyl chloride R 8 SO 2 Cl, in the presence of a base, optionally in the presence of a solvent.

Procedures for carrying out the reactions described above are well known to those skilled in the art and/or are illustrated herein. In any of the reactions described herein, reactive substituent groups or sites in the molecule may be protected prior to reaction, using appropriate protecting groups which are inert to the reaction conditions and which are removed after the reaction.

Compounds of the invention may conveniently be prepared using conventional methods of synthesis and, if necessary, standard separation and isolation techniques. For example, compounds of formula I, where Q is SO 2 , n is 2 and R 3 and R 4 are H (1a), can be prepared by sequentially reacting an indole derivative of formula I with oxalyl chloride and an amine, HNR 5 R 6 , to give the intermediate of formula III; reducing the carbonyl groups of formula III with lithium aluminum hydride to give the corresponding 3-ethylamine derivative of formula IV; and reacting said formula IV derivative with a base, such as potassium t-butoxide or sodium hydride, followed by a sulfonyl chloride, R 8 SO 2 Cl, giving the desired product of formula la. The reaction sequence is shown in flow diagram I.

For intermediates of formula IV, where R5 or R6 is H, the formula IV amine can be protected with a conventional protecting reagent, such as di-t-butyl carbonate, prior to the final sulfonylation steps. The resulting N-protected compound of formula I can then be deprotected in the presence of an acid.

Alternatively, compounds of formula la can be prepared by reacting a 3-(2-bromomethyl) derivative of formula V sequentially with a base and a sulfonyl chloride, R 8 SO 2 Cl, giving the intermediate of formula Vl, and reacting the intermediate of formula Vl with an amine, HNR5R6, which gives the desired product of formula la. The reaction steps are shown in flow diagram II.

Compounds of formula I, where R 3 or R 4 is different from H and Q is SO 2 (Ib), can be prepared by sequentially reacting the intermediate of formula II with a Grignard reagent, such as ethylmagnesium bromide, and an amino acid chloride of formula VII, giving the 3 -acylated the compound of formula VIII; reducing said compound of formula VIII with a reducing agent such as lithium aluminum hydride to give the corresponding 3-alkylamino compound of formula IX, and sulfonating the compound of formula IX as described above in flow charts I and II to give the desired formula lb product. The reaction sequence is shown in flow diagram III.

In the case where R 5 or R 6 is H, the nitrogen atom of the amino acid chloride of formula VII is protected, and the corresponding resulting product can be deprotected using conventional auxiliaries, yielding the desired formula 1b compound, where R 5 or R 6 is H.

Compounds of formula I, where Q is SO 2 , n is 3 and R 3 , R 4 , R 5 , R 6 and R 7 are H (le) can be prepared by sequentially reacting an arylhydrazine hydrochloride of formula X with 3,4-dihydro-2H-pyran , giving indol-3-ylpropanol-1-ol of formula XI; replacing the hydroxy group with bromine, giving the corresponding bromo compound of formula XII; reacting the compound of formula XII with sodium azide to give the azide of formula XIII; to sulfonylate the azide of formula XIII, giving the compound of formula XIV, and to convert the compound of formula XIV to the desired amine of formula le via reaction with triphenylphosphine. The reaction sequence is shown in flow chart IV.

Protecting groups useful in the reactions described above include t-butyl carboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group known to protect a basic nitrogen in standard synthetic procedures.

Sulfonyl chlorides, RgSO4Cl, can be obtained commercially or prepared by conventional techniques. For example, 6-substituted-imidazo[2,1-b][1,3]-thiazol-5-ylsulfonyl chlorides of formulas Xva and XVb can be prepared by reacting 2-aminothiazole with chloroacetic acid or a suitable chloromethyl ketone, giving respectively 2-imino-4-thiazolin-3-ylacetic acid (XVIa), or the 2-imino-4-thiazolin-3-yl ketone (XVIb); reacting either XVIa or XVIb with POCI3 to give, in the case of XVIa, 6-chloroimidazo[2,1-b]thiazole (XVIIa), or, in the case of XVIb, 6-substituted-imidazo[2,1-b ]thiazole (XVIIb); and sequentially reacting, respectively, the compounds of formula XVIIa and XVIIb with chlorosulfonic acid and POCl3, which gives the desired sulfonyl chlorides of formulas XVa and XVb. The reactions are illustrated in flow chart V, where R represents any substituent as described above, with the exception of halogen.

Advantageously, the present invention provides a process for the preparation of a compound of formula I, where Q is SO2 and R5 and R6 is different from H (Id), which comprises reacting a compound of formula XVIII with a sulfonyl chloride, R8SO2CI, in the presence of a base, optionally in the presence of a solvent. The procedure is shown in flowchart VI.

Bases suitable for use in the methods of the invention are strong bases, such as NaH, Kot-Bu, or any conventional base capable of removing a proton from a basic indole or benzazole nitrogen atom.

Advantageously, the compound of formula I according to the invention can be used in the treatment of disorders in the central nervous system which are related to, or affected by, the 5-HT6 receptor, such as motor disorders, mood disorders, psychiatric disorders, cognitive disorders, neurodegenerative disorders or similar disorders, for example, Alzheimer's disease, Parkinson's disease, ADD, anxiety, epilepsy, depression, OCD, migraine, sleep disorders, neurodegenerative disorders (such as head trauma or stroke), eating disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawal after drug or nicotine abuse, or the like, or certain gastrointestinal disorders, such as irritable bowel syndrome.

Accordingly, the present invention provides the use of a compound of formula I or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for use in the treatment of a disorder of the central nervous system which is related to, or affected by, 5-HT6 -receptor in a patient who needs this. The patient may be administered a therapeutically effective amount of a compound of Formula I. The compounds may be administered by oral or parenteral administration, or by any conventional means known to be effective in administering a therapeutic agent to a patient in need thereof before.

The therapeutically effective amount administered in the treatment of a specific SNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician, and the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg, and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.

In treatment, the compounds according to the invention are given by administering the compound, or a precursor thereof, in solid or liquid form, either pure or in combination with one or more conventional pharmaceutical carriers or excipients.

Accordingly, the present invention provides a pharmaceutical preparation comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula formula I, as described above, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Carriers in solid form which are suitable for use in the preparation according to the invention include one or more substances which can also serve as flavoring agents, lubricants, solubilizers, suspending agents, fillers, lubricants, compression aids, binders, tablet disintegrants or encapsulating materials. In powders, the carrier can be a finely divided solid which is mixed with a finely divided compound of formula 1.1 tablets, the formula 1 compound can be mixed with a carrier that has the necessary compression properties in suitable proportions and compacted in the desired shape and size. The aforementioned powders and tablets can contain up to 99% by weight of the compound of formula I. Solid carriers suitable for use in the preparation according to the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose , sodium carboxymethyl cellulose, polyvinylpyrrolidine, low-melting wax types and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for the preparation of solutions, suspensions, emulsions, syrups and elixirs can be used in the preparation according to the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. The aforementioned liquid preparation may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, coloring agents, viscosity-regulating agents, stabilizing agents, osmoregulating agents, etc. Examples of liquid carriers suitable for oral and parenteral administration include water (especially containing additives as above, for example cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols), or their derivatives, or oils (for example fractionated coconut oil and arachis oil). For parenteral administration, the carrier may also be an oily ester, such as ethyl oleate or isopropyl myristate.

Preparations according to the invention, which are sterile solutions or suspensions, are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Preparations according to the invention which are suitable for oral administration can be in either liquid or solid preparation form.

For a clearer understanding, and to illustrate the invention more clearly, specific examples thereof are set forth below.

Unless otherwise stated, all parts are by weight. The terms NMR and HPLC stand for nuclear magnetic resonance and high-performance liquid chromatography, respectively. The terms THF and EtOAc mean tetrahydrofuran and ethyl acetate, respectively.

EXAMPLE 1

Preparation of 2{1-r(6-chloroimidazor2,1-biri,31thiazol-5-vl)sulfonvn-1H-indole-3-vDetvlamine-hydrochloride.

A solution of tryptamine (4.2 g, 26.2 mmol) in a 1:1 mixture of acetone:water is treated with di-t-butyl carbonate (6.5 g, 27.8 mmol) and K 2 CO 3 (7, 5 g, 54.4, mmol), stirred at room temperature for 16 h, evaporated under vacuum to an aqueous mixture and extracted with EtOAc. The extracts are combined, dried over MgSO4 and evaporated under vacuum. A mixture of the resulting residue (5.6 g, 21 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (5.01 g, 19.5 mmol) in THF is treated portionwise with potassium -t.butoxide (4.3 g, 39 mmol (2 equiv) at room temperature, stirred for 16 h, poured into a saturated NaHCO 3 solution and extracted with EtOAc. The extracts are combined, dried over MgSO 4 and evaporated under vacuum. This the resulting residue is chromatographed (silica gel, 10%-60% EtOAc in hexanes as gradient eluent) to afford the protected 5-sulfonyltryptamine intermediate as a tan solid, 5.6 g (60% yield). the intermediate (6.8 g, 14.2 mmol) in isopropanol is treated with 4N HCl in dioxane (40 mL, 11 equiv), stirred for 4 h and filtered.The filter cake is washed with ether and air dried to give the title product as a Off-white solid, 3.2 g (55% yield), mp 239-241 °C, identified by NM R and mass spectral analysis.

REFERENCE EXAMPLE 2

Preparation of 3-(2-bromomethyl)-1-(6-chloroimidazol-2,1-bithiazole-5-sulfonyl)indole.

A mixture of 3-(2-bromomethyl)indole (1.0 g, 4.46 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.96 g, 1.1 equiv) in THF, treated with potassium t-butoxide (0.48 g, 1.1 eq.) at room temperature, stirred for 16 h, treated with saturated NaHCO 3 , and extracted with EtOAc. The extracts are combined, dried over MgSO 4 and evaporated in vacuo to give the title product as a brown oil, 1.2 g (58% yield), identified by HPLC and mass spectral analysis.

EXAMPLE 3

Preparation of 12-M-(6-chloroimidazol-2,1-bithiazole-5-sulfonyl)-1H-indole-3-yl-ethylmethylmethylamine.

A solution of 3-(2-bromomethyl)-1-(6-chloroimidazo[2,1-b]thiazole-5-sulfonyl)indole (92 mg, 0.20 mmol) in THF is treated with methylamine (2M in methanol, 0.4 mL, 2 equiv.), heated at 50°C for 24 h, cooled and evaporated under vacuum. The resulting residue is purified by HPLC<1> to give the title product as a white solid, 18.5 mg, identified by HPLC<2> and mass spectral analysis.

<1>HPLC conditions (preparative): Gilson Preparative HPLC system; YMC Pro C18, 20 mm x 50 mm ID, 5 µM column; 2 ml injection; solvent A: 0.02% TFA/water; solvent B: 0.02% TFA/acetonitrile; gradient: time 0: 95% A; 2 min.: 95% A; 14 min.: 10% A, 15 min.: 10% A, 16 min.: 95% A; flow rate 22.5 ml/min.; detection: 254 nm DAD.

<2>HPLC conditions (analytical): Hewlett Packard 1100 HPLC system; Waters Xterra C18, 2 mm x 30 mm ID, 3 µM column; 5 ul injection; solvent A: 0.02% TFA/water; solvent B: 0.02% TFA/acetonitrile; gradient: time 0: 95% A; 0.2 min.: 95% A; 3 min.: 5% A; flow rate 1.2 ml/min.; detection: 254 nm DAD.

EXAMPLE 4-11

Preparation of N-substituted-2-{1-r(6-chloroimidazor2,1-bin,31thiazole-5-vD-sulfonyl-1H-indole-3-yl)ethylamine derivatives.

Using substantially the same procedures as described above and using the appropriate amine, the compounds shown in Table I are obtained and identified by HPLC and mass spectral analysis.

EXAMPLE 12

Preparation of 2ri-(6-chloroimidazor2,1-blthiazole-5-sulfonyl)-1H-indole-3-yl1-1-metvletvlamine hydrochloride.

A solution of α-methyltryptamine methanesulfonate (5.0 g, 18.5 mmol) in a 1:1 mixture of acetone:water is treated with di-t-butyl dicarbonate (7.7 g, 55.5 mmol, 3 eq.), stirred at room temperature for 16 h, evaporated to an aqueous mixture and extracted with EtOAc. The extracts are combined, dried over MgSO 4 and evaporated under vacuum. A mixture of a portion of the resulting residue (2.0 g, 7.3 mmol, 1.1 equiv) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (1.7 g, 6, 6 mmol, 1.0 equiv) in THF, is treated portionwise with potassium t-butoxide (820 mg, 7.3 mmol, 1.1 equiv) at room temperature, stirred for 1 h, poured into saturated NaHCO 3 and extracted with EtOAc . The extracts are combined, dried over Na 2 SO 4 and evaporated under vacuum. This resulting residue is chromatographed (silica gel, 20%-50% EtOAc in hexanes as gradient eluent) to give the free base of the title product as a brown oil, 1.7 g (50% yield). Treatment with 4N HCl in dioxane and THF, followed by filtration and recrystallization of the filter cake from ethanol gave the title product as a light brown solid, 1.0 g (40% yield), identified by NMR and mass spectral analysis.

REFERENCE EXAMPLE 13

Preparation of (S)-2-amino-1-(1H-indol-3-vl)propan-1-one.

A solution of indole (1.1 g, 9.3 mmol, 1.0 equiv) in methylene chloride under N 2 at 0°C is treated dropwise with ethylmagnesium bromide (9 mL 3.OM in ether, 27 mmol, 3 equiv) , is allowed to warm to room temperature for 1 hour, is cooled to 0°C, treated dropwise with a solution of Fmoc-L-alanine chloride (14.0 mmol, 1.5 eq.) in methylene chloride, is allowed to be warmed to room temperature for 1 hour, is poured over 50 ml of aqueous 1N HCl, cooled to 0°C and stirred at 0°C for 15 minutes. The phases are separated. The organic phase is dried over Na 2 SO 4 and evaporated under vacuum, giving a residue. The residue is diluted with saturated NaHCO 3 and extracted with EtOAc. The extracts are combined and evaporated under vacuum, giving a residue which is dissolved in 10% piperidine in dimethylformamide and stirred for 1 hour at room temperature. The resulting solution is diluted with saturated NaHCO 3 and extracted with EtOAc. The extracts are combined, dried over MgSO 4 and evaporated in vacuo to give the title product as a brown oil, 0.8 g (47% yield), identified by HPLC and mass spectral analysis.

REFERENCE EXAMPLE 14

Preparation of (S)-2-(1H-indole-3-vl)-1-methylethylamine.

A solution of (S)-2-amino-1-(1H-indol-3-yl)propan-1-one (0.47 g, 2.5 mmol, 1.0 eq.) in acetonitrile and isopropanol, is treated portionwise with NaBH 4 (285 mg, 7.49 mmol, 3.0 equiv), heated at reflux for 24 h, stirred at rt under N 2 in 36 h, treated with methanol, evaporated and partitioned between water and EtOAc. The EtOAc phase is dried over MgSO 4 and evaporated in vacuo to give the title product as a brown oil, identified by HPLC and mass spectral analysis.

EXAMPLE 15

Preparation of (S)-2-ri-(6-chloroimidazol2.1-blthiazole-5-sulfonyl)-1H-indole-3-yl-1-methylethylamine hydrochloride.

A mixture of (S)-2-(1H-indol-3-yl)-1-methylethylamine (0.43 g, 2.5 mmol) and di-t-butyl dicarbonate (0.60 g, 2.75 mmol) in acetone, is treated dropwise with aqueous K2CO3 (3.5 g, 25 mmol) at 0°C, allowed to warm to room temperature for 16 h, evaporated to an aqueous residue and extracted with EtOAc. The extracts are combined, dried over MgSO 4 and evaporated under vacuum to dryness. This residue is chromatographed (silica gel, 10%-50% EtOAc in hexanes as gradient eluent) to give the protected (R)-2-methyltryptamine. A mixture of the protected tryptamine (0.17 g, 0.62 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.16 g, 0.62 mmol) in THF is treated with potassium t-butoxide (77 mg, 0.68 mmol) at room temperature, stirred for 1 h, poured into saturated NaHCO 3 and extracted with EtOAc. The extracts are combined, dried over Na 2 SO 4 and evaporated under vacuum. The resulting residue is dispersed in THF and 4N HCl in dioxane, stirred for 16 h, evaporated in vacuo and purified by HPLC<1> to give the title product as a beige solid, 0.62 mg (35% yield), identified by of NM R and mass spectral analysis.

<1>HPLC conditions: Hewlett Packard 1100 HPLC system; Waters Xterra C18, 2 mm x 30 mm ID, 3 µM column; 5 ul injection; solvent A: 0.02% TFA/water,

solvent B: 0.02% TFA/acetonitrile; gradient: time 0: 95% A; 0.2 min.: 95% A; 3 min.: 5% A; flow rate 1.2 ml/min.; detection: 254 nm DAD.

EXAMPLE 16

Preparation of (R)-2-ri-(6-chloroimidazol2.1-blthiazole-5-sulfonyl)-1H-indole-3-yl-1-methylmethylamine hydrochloride.

Using substantially the same procedures as described above, and using F-moc-D-alanine as starting material, the title product is obtained and identified by HPLC and mass spectral analysis.

EXAMPLES 17-40

Preparation of indolylalkylamine derivatives.

Using substantially the same procedures as described above, and using the appropriate indole substrate and sulfonyl halide, the compounds shown in Table II are obtained and identified by HPLC and mass spectral analysis.

REFERENCE EXAMPLE 41

Preparation of 3-(fluoro-1H-indol-3-vl)propan-1-ol.

A stirred suspension of 4-fluorophenylhydrazine hydrochloride (8.13 g, 50 mmol) in a mixture of water and dioxane is treated with a solution of 3,4-dihydro-2H-pyran (4.6 mL, 50 mmol) in over a period of 5 min., heated at 100°C for 18 h, cooled, diluted with ether and filtered. The filtrate is dried over NaSO and evaporated under vacuum. The resulting residue is purified by flash chromatography (silica gel, 1:1 EtOAc/hexane) to give the title product as an oil, 8.31 g (86% yield), identified by NMR and mass spectral analysis.

REFERENCE EXAMPLE 42

Preparation of 3-(3-bromopropyl)-5-fluoro-1H-indole.

A mixture of 3-(5-fluoro-1H-indol-3-yl)propan-1-ol (2.15 g, 11.2 mmol), carbon tetrabromide (4.80 g, 14.5 mmol) and triphenylphosphine ( 4.40 g, 16.7 mmol) in methylene chloride, is stirred for 1 hour and evaporated under vacuum. The resulting residue is purified by flash chromatography (silica gel, EtOAc/hexane 3/7) to give the title product as an oil, 1.97 g (69% yield), identified by NMR and mass spectral analysis.

REFERENCE EXAMPLE 43

Preparation of 3-(3-azidopropyl)-5-fluoro-1H-indole.

A solution of 3-(3-bromopropyl)-5-fluoro-1H-indole (0.95 g, 3 mmol) and sodium azide (0.59 g, 9 mmol) in anhydrous dimethylformamide is stirred at 60°C for 18 hours, poured into water and extracted with methylene chloride. The extracts are combined, washed with water, dried over Na 2 SC* 4 and evaporated under vacuum. The resulting residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to give the title product as a clear oil, 0.98 g (91% yield), identified by NMR and mass spectral analysis.

REFERENCE EXAMPLE 44

Preparation of 3-(3-azidopropyl)-1-r(6-chloroimidazor2.1-blH,31thiazol-5-yl)sulfonvn-5-fluoro-1H-indole.

A stirred solution of 3-(3-azidopropyl)-5-fluoro-1H-indole (150 mg, 0.53 mmol) in THF is treated with Kot-Bu (0.55 mL, 0.55 mmol, 1M in THF solution) under nitrogen at room temperature, stirred for 30 min, treated with 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (141 mg, 0.55 mmol), stirred for 18 h at room temperature, treated with 1N HCl and water and diluted with EtOAc. The two phases are separated and the aqueous phase is extracted with EtOAc. The extracts are combined with the organic phase and dried over MgSO 4 and evaporated under vacuum. The resulting residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to give the title product as a yellow solid, 203 mg (88% yield), m.p. 84-86°C, identified by NMR and mass spectral analysis.

EXAMPLE 45

Preparation of 3-{1-r(6-chloroimidazor2,1-blM,31thiazol-5-vl)sulfonvl1-5-fluoro-1H-indole-3-vl)propane-1-amine.

A mixture of 3-(3-azidopropyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)-sulfonyl]-5-fluoro-1H-indole (180 mg, 0.41 mmol) and triphenylphosphine (161 mg, 0.62 mmol) in THF and water, is stirred under nitrogen for 24 h at room temperature and evaporated under vacuum. The resulting residue is purified by flash chromatography (silica gel, EtOAc/2M NH3 in MeOH: 98/2) to give the title product as an off-white solid, 132 mg (78% yield), m.p. 139-141°C, identified by NMR and mass spectral analysis.

EXAMPLE 46

Comparative assessment of 5-HT6 binding affinity of test compounds.

The affinity of the test compounds for the serotonin-5-HT6 receptor is assessed in the following way. Cultured Hela cells expressing human cloned 5-HT6 receptors are harvested and centrifuged at low speed (1,000 x g) for 10.0 minutes to remove the culture medium. The harvested cells are suspended in half a volume of freshly prepared, physiological, phosphate-buffered saline solution and again centrifuged at the same speed. This operation is repeated. The collected cells are then homogenized in ten volumes of 50 mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at 40,000 x g for 30.0 minutes and the precipitate is collected. The pellet obtained is resuspended in 10 volumes of Tris.HCl buffer and again centrifuged at the same speed. The final pellet is suspended in a small volume of Tris.HCl buffer and the tissue protein content is determined in aliquots of 10-25 µl parts by volume. Bovine serum albumin is used as a standard in the protein determination, in accordance with the method described in Lowry et al., J. Biol. Chem., 193:265 (1951). The volume of the suspended cell membranes is adjusted to give a tissue protein concentration of 1.0 mg/ml of suspension. The prepared membrane suspensions (concentrated 10 times) are aliquoted in 1.0 ml volumes and stored at -70°C, until used in subsequent binding experiments.

Binding experiments are performed in a 96-well microtiter plate format, in a total volume of 200. To each well is added the following mixture: 80.0 µl incubation buffer prepared in 50 mM Tris.HCl buffer (pH 7.4) containing 10 .0 mM MgCfe and 0.5 mM EDTA and 20 µl [<3>H]-LSD (S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. The dissociation constant, Kd for [<3>H]LSD at the human serotonin-5-HT6 receptor is 2.9 nM, as determined by saturation binding with increasing concentrations of [<3>H]LSD. The reaction is initiated by the final addition of 100.0 µl of tissue suspension. Non-specific binding is measured in the presence of 10.0 µM methiothepin. The test compounds are added in a 20.0 µl volume.

The reaction is allowed to proceed in the dark for 120 minutes at room temperature, at which time the bound ligand-receptor complex is filtered off onto a 96-well unifilter with a Packard Filtermate<®>196 Harvester. The bound complex captured on the filter disc is allowed to air dry and the radioactivity is measured with a Packard TopCount<®> equipped with six photomultiplier detectors, after the addition of 40.0 µl of Microscint<®>20 scintillator to each shallow well. The unifilter plate is heat-sealed and counted in a PackardTopCount<®> with a tritium efficiency of 31.0%.

Specific binding to the 5-HT 6 receptor is defined as the total radioactivity bound, minus the amount bound in the presence of 10.0 µM unlabeled methiothepine. Binding in the presence of varying concentrations of test compound is expressed as a percentage of specific binding in the absence of test compound. The results are plotted as log % bound against log concentration of test compound. Non-linear regression analysis of data points with a computer-assisted program, Prism®, provided both the IC 50 and Kr values for the test compounds with 95% confidence limits. A linear regression line of data points is plotted, from which the IC50 value is determined and the Kr value is determined, based on the following equation:

where L is the concentration of the radioactive ligand used and KD is the dissociation constant of the ligand for the receptor, both expressed as nM.

Using this assay, the following Ki values are determined and compared to values obtained with representative compounds known to exhibit binding to the 5-HT 6 receptor. The data are shown in Table III below.

As can be seen from the results presented above, the compounds of the present invention exhibit significant affinity for the 5-HT6 receptor.

Claims (15)

1. Connection, characterized in that it has formula I where Q is SO2, n is an integer of 2 or 3, R 1 and R 2 are each, independently, H, halogen, C 1 -C 6 -alkyl, hydroxy, C 1 -C 6 - alkoxy or C 1 -C 6 alkoxy substituted with phenyl; R 3 and R 4 are each, independently, H or C 1 -C 6 -alkyl, R 5 and R 6 are each, independently, H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with fe nyl, or R5 and R6 can, together with the atom to which they are attached, form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally substituted with C1-C6 alkyl or COOH; R7 is H, R8 is an imidazo[1,2-a]pyridine, imidazo[2,1-b][1,3]thiazolyl or benzo[d]- imidazo[2,1-b][1,3]thiazole ring system optionally substituted with 0-3 substituents selected from halogen and C1-C6 alkyl; or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, where n is 2. 3. A compound according to claim 1, wherein R8 is 6-chloroimidazo[2,1-b][1,3]thiazol-5-yi- 4. Compound according to claim 1, wherein R3 and R4 are H. 5. A compound according to claim 1, wherein R5 and R6 are each hydrogen. 6. Compound according to claim 1, selected from: 2-{1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indol-3- yl}ethylamine, 2-{1-[(imidazo[2,1-b][1>3]thiazol-5-yl)sulfonyl]-1H-indol-3-yl}ethylamine>{2-[1 -( 6-chloroimidazo[2,1 -b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1 -(6-chloroimidazo[2,1 - b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}dimethylamine, benzyl{2-[1-(6-chloroimidazo[2,1-b][1,3] thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}amine, 1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-3-(2- pyrrolidin-1-ylethyl)-1H-indole, 1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-3-[2-(4-methylpiperazin-1-yl )ethyl]-1H-indole, 1-(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-3-(2-piperidin-1-ylethyl)-1H-indole, benzyl{2-[1 -(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1 -( 6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}phenethylamine, 1- {2-[1-(6-chloroimidazo[2, 1-b][1,3]thiazol-5-sulfonyl) 1 H-indol-3-yl]ethyl}pyrrolidine-2-carboxylic acid, 2- [1 -( 6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]-1-methylethylamine, (R)-2-[1-(6-chloroimidazo[ 2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]-1-methylethylamine, (S)- 2-[1-(6-chloroimidazo[2,1- b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]-1-methylethylamine, 2-[1-(2-chloroimidazo[2,1-a]pyridine-3-sulfonyl] -1H-indol-3-yl]ethylamine, 2-[1-(2,6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl] Ethylamine, 2-[1 -(2-chlorobenzo[d]imidazo[2,1-b][1,3]thiazol-3-sulfonyl)-1H-indol-3-yl]ethylamine, {2-[1 -(2-chloroimidazo[2,1-a]pyridin-3-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1-(2,6-dichloroimidazo[2,1-b] [1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1 -(2-chlorobenzo[d]imidazo[2,1-b][1,3] thiazol-3-sulfonyl)-1H-indol-3-yl]ethyl}methylamine, {2-[1-(2-chloroimidazo[2,1-a]pyridine-3-sulfonyl)-1H-indol-3 -yl]ethyl}dimethylamine, {2-[1-(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethyl}dimethylamine, {2-[1-(2-Chlorobenzo[d]imidazo[2,1-b][1,3]thiazol-3-sulfonyl)-1H-indol-3-yl]ethyl}di methylamine, 2-[5-chloro-1-(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5 -chloro-1-(2-chloroimidazo[1,2-a]pyridin-3-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5-chloro-1-(2,6-dichloroimidazo[ 2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5-chloro-1-(2-chlorobenzo[d]imi^amine, 2-[1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-5- methoxy-1H-indol-3-yl]ethylamine, 2-[1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl-6-methoxy-1H-indol-3-yl ]ethylamine, 2-[5-bromo-1-(6-chloroimidazo[2>1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[5- benzyloxy-1-(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-1H-indol-3-yl]ethylamine, 2-[1-(6-chloroimidazo[ 2,1-b][1,3]thiazole-5-sulfonyl)-5-methyl-1H-indol-3-yl]ethylamine, 2-[1-(6-chloroimidazo[2,1-b][ 1,3]thiazole-5-sulfonyl)-6-methyl-1H-indol-3-yl]ethylamine, 2- [1-(6-chloroimidazo[2,1-b][1,3]thiazole-5 -sulfonyl)-7-methyl-1H-indol-3-yl]ethylamine, 3-(2-aminoethyl)-1-(6-chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl )1H-indol-5-ol, 2-[1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-5-fluoro-1H-indol-3-yl ]ethylamine, 2- [1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-6-fluoro-1H-indol-3-yl]ethylamine, 1-(6 -chloroimidazo[2,1-b][1,3]thiazol-5-sulfonyl)-3-(2-morpholin-4-ylethyl)-1H-indole, 3- {1 -[(6-chloroimidazo[2 ,1 -b][1, 3]thiazol-5-yl)sulfonyl]-5-fluoro-1H-indol-3-yl}propan-1-amine, the stereoisomers thereof, and the pharmaceutically acceptable salts thereof. 7. Use of a compound of formula I, as set forth in any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical preparation for use in the treatment of a disorder of the central nervous system which is related to, or affected by, the 5-HT6 receptor in a patient in need thereof. 8. Use according to claim 7, where the said disorder is a motor disorder, anxiety disorder or cognitive disorder. 9. Use according to claim 7, wherein said disorder is schizophrenia or depression. 10. Use according to claim 8, where the said disorder is Alzheimer's disease or Parkinson's disease. 11. Use according to claim 8, wherein said disorder is attention deficit disorder or obsessive compulsive disorder. 12. Pharmaceutical preparation, characterized in that it comprises a pharmaceutically acceptable carrier and a compound of formula I, as set forth in any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 13. Process for preparing a compound of formula I as defined in claim 1, characterized in that it comprises one of the following: a) to convert a compound of formula B: where n, R, R2, R3, R4, R5, R6 and R7 are as defined in claim 1, with a suitable sulfonylating agent containing the group: where R 8 is as defined in claim 1 and Q is SO 2 ; the reactants being protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups, which gives a corresponding compound of formula I; or b) removing a protecting group from a compound of formula I, wherein R 5 is a protecting group, yielding a corresponding compound of formula I, wherein NR 5 Re is -NHR 6 ; or c) to react a compound of formula (C): where Q, n, R1fR2, R3, R4, R7 and R8 are as defined in claim 1 and L is a leaving group, such as halogen, with an amine of formula HNR5R6, giving a corresponding compound of formula I; or d) converting a compound of formula I having a reactive substituent group into another compound of formula I; or e) converting a basic compound of formula I into an acid addition salt, or vice versa; or f) isolating an isomer of a compound of formula I from a mixture of isomers; or g) converting an azide of formula (D) where Q, n, R 1 , R 2 , R 3 , R 4 , R 7 and R s are as defined herein, to a corresponding compound of formula I, where R 5 and R 6 are both H. 14. Process for preparing a compound of formula Id where n is an integer of 2 or 3, R 1 and R 2 are each, independently, H, halogen, C 1 -C 6 -alkyl, hydroxy, C 1 -C 6 - alkoxy, or C 1 -C 6 alkoxy substituted with phenyl; R 3 and R 4 are each, independently, H or C 1 -C 6 alkyl, R 5 and R 6 are each, independently, H, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl substituted with fe nyl, or R 5 and R 6 may be taken together with the atom to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally substituted with C 1 -C 6 alkyl or COOH; R7er H, R8 is an imidazo[1,2-a]pyridine, imidazo[2,1-b][1,3]thiazolyl or benzo[d]- imidazo[2,1-b][1,3]thiazole ring system optionally substituted with 0-3 substituents selected from halogen and C1-C6 alkyl; characterized in that it comprises reacting a compound of formula XVIII where n, R-i, R2, R3, R4, R5, R6 and R7 are as defined above for formula Id, with a sulfonyl chloride R8SO2Cl, in the presence of a base, optionally in the presence of a solvent. 15. Compound according to claim 6, being 2-{1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-indol-3-yl}ethylamine .